The aims of this proposal concern studies aimed at a better understanding of virus persistence, latency and reactivation and their role in virus oncogenesis. A multidisciplinary approach involves scientists with expertise in cell biology, virology, immunology, molecular biology, genetics, oncology, and pathology. Focus of the program is on human herpesviruses and human papillomaviruses although other viruses will also serve as model system when indicated. The studies proposed will examine molecular events involved in latency and reactivation of herpes simplex virus, including gene sequences and products able to activate virus replication and properties of cells and virus restricting virus replication. These phenomenon may be critical in maintenance of the latent state, which may be a prelude to transformation. The immune response to virus infection and to tumor cells will be dissected to determine events at the molecular level that enable escape from immune surveillance, clearly important for progression to malignancy. Chronic virus infections, often in the presence of an immune responce, represent a major hurdle in control of infectious disease. Herpes simplex virus latency, long the prototype of such a condition, is now known to be only one of many viruses that can remain laten in the human host. The immune deficiency virus represents another major group that can persist for an extended period of time following infection and it is possible that many chronic degenerative central nervous system disorders (i.e., multiple sclerosis, Alzheimer's disease) have a virus component as a causal factor. Hence, information obtained in this program may well be relevant to the general problem of control of chronic virus infections.